Original Article EFFICACY AND SAFETY OF DUTASTERIDE IN CLINICAL PRACTICE DESGRANDCHAMPS et al.

Effect of dutasteride on the symptoms of benign prostatic hyperplasia, and patient quality of life and discomfort, in clinical practice FRANÇOIS DESGRANDCHAMPS, STEPHANE DROUPY*, JACQUES IRANI†, CHRISTIAN SAUSSINE‡ and ANDREA COMENDUCCI¶ Departments of Urology, Saint Louis Hospital, Paris, *CHU Bicêtre, Kremlin-Bicêtre, †La Miletrie Hospital, Poitiers, ‡CHU des Hospices Civils, Strasbourg and ¶Department of Internal Medicine and Clinical Pharmacology, GlaxoSmithKline, Marly-le-Roi, France Accepted for publication 3 March 2006

OBJECTIVE To assess the improvements in symptoms, quality of life (QoL), discomfort and satisfaction in patients with symptomatic benign prostatic hyperplasia (BPH) treated with dutasteride in clinical practice.

treatment. The secondary endpoints included changes from baseline in measures of QoL (IPSS item 8 and BPH Impact Index score, BII), and patient discomfort and satisfaction (visual analogue scales, VAS) at 12 and 24 weeks.

(P < 0.001) improvements in the BII and VAS scores for patient discomfort and satisfaction at both times.

RESULTS

Dutasteride treatment for 24 weeks significantly improved BPH symptoms, QoL and patient discomfort and satisfaction, and was well tolerated in clinical practice.

PATIENTS AND METHODS In a prospective, multicentre open-label study, we evaluated the efficacy and safety in clinical practice of dutasteride, 0.5 mg/day for 24 weeks, in patients with symptomatic BPH. The primary endpoint was the proportion of patients achieving at least a 3-point decrease from baseline in the International Prostate Symptom Score (IPSS) after 24 weeks of

INTRODUCTION BPH is a common condition in ageing men, affecting over half of men in their seventh decade and 90% of men in their eight and ninth decade [1]. The condition is characterized histologically by stromal and epithelial hyperplasia [2,3], and clinically by LUTS, which are typically divided into irritative (storage) symptoms (i.e. increased frequency, nocturia and urgency) and obstructive (voiding) symptoms (i.e. incomplete emptying, weak stream, intermittency and hesitancy). Disease progression can lead to worsening of LUTS and a greater risk of acute urinary retention (AUR) and BPH-related surgery [4]. Thus, the aims of therapy for BPH are to provide symptom relief and improve the quality of life (QoL) of patients, while also reducing the risk of severe, long-term BPHrelated complications. 5α-reductase inhibitors (5ARIs) specifically inhibit the conversion of testosterone into

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Of the 366 patients assessed, 72.5% achieved at least a 3-point reduction in IPSS at 24 weeks; the IPSS decreased from 15.3 at baseline to 10.2 at 12 weeks, and to 9.1 at 24 weeks. There were significant (P < 0.001) decreases in all the individual IPSS items at 12 and 24 weeks, with more marked improvements in voiding symptoms than storage symptoms. There were also significant

dihydrotestosterone, the primary androgen responsible for prostate growth, and reduce significantly the risk of long-term BPHrelated complications [4,5]. The enzyme 5αreductase exists in two isoforms, type 1 and type 2. Finasteride is a type 2-specific 5ARI, while dutasteride is a dual-acting 5ARI. Inhibition of both the type 1 and type 2 isoenzymes with dutasteride results in nearmaximal suppression of dihydrotestosterone (>90%), which is evident within a few weeks and sustained for up to 48 months [6,7]. Large, prospective, randomized, placebocontrolled trials showed that in men with symptomatic BPH, dutasteride provides significant improvements in symptoms and peak urinary flow rate and significant reductions in prostate volume and the risk of AUR and BPH-related surgery over 4 years of treatment [8,9]. In these studies, dutasteride also had a favourable safety profile. While these clinical trials provide robust statistical evidence of the efficacy and safety of dutasteride in this setting, confirmation of the

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CONCLUSIONS

KEYWORDS BPH, IPSS, discomfort, quality of life, BII, visual analogue scale, 5α-reductase inhibitor, dutasteride

impact of dutasteride in real-life clinical practice is warranted [10]. The extent to which results from clinical trials can be generalized to clinical practice can be limited by several factors, e.g. the restrictive inclusion and exclusion criteria, close monitoring, restrictions on concomitant therapy and lack of variation in dosing commonly implemented in clinical trials. In addition, efficacy endpoints in clinical trials might not reflect measures of treatment success, as judged by patients. Treatment satisfaction has important implications for patient compliance and therefore the overall treatment success rate in clinical practice. BPH is known to cause a deterioration in QoL and increase patient discomfort [11,12], and, in recognition of the importance of patient discomfort and satisfaction, BPH guidelines now recommend that patients are involved in discussions on the choice of therapeutic approach [13–15]. In the current study we evaluated the effect of dutasteride, 0.5 mg once daily for 83

D E S G R A N D C H A M P S ET AL.

24 weeks, on symptoms, QoL and patient discomfort and satisfaction among men with symptomatic BPH in real-life clinical practice.

PATIENTS AND METHODS This was a French prospective, multicentre, noncomparative study of patients receiving dutasteride, 0.5 mg once daily for 24 weeks, in French clinical practice. The efficacy and safety endpoints were assessed at screening, baseline, 12 and 24 weeks of treatment; safety data were also collected at an intermediary visit at 4 weeks. The final followup was at 16 weeks after the final dose. The study protocol was approved by the Ethics Committee of the Saint Louis Hospital (Paris, France) and all patients provided written, informed consent. Patients aged ≥50 years with symptomatic BPH and a minimum prostate volume of 30 mL, estimated by a DRE, were included in the study. Patients with a history of prostate cancer, prostate surgery or AUR within 6 months before study entry, those previously treated with 5ARIs, and those who had received α-blockers, phytotherapy, drugs with anti-androgenic properties, or anabolic steroids within the 2 weeks before study entry were excluded. The primary endpoint was the proportion of patients reporting a decrease of ≥3 points in the IPSS [16] after 24 weeks of treatment. Secondary endpoints included changes from baseline at 12 and 24 weeks in the following variables: mean IPSS (0–7, 8–19 and 20–35, representing mild, moderate and severe symptoms, respectively); mean voiding symptom (IPSS Q1, 3, 5 and 6) and storage symptom (IPSS Q2, 4 and 7) subscores; mean BPH Impact Index score (BII, graduated from 0 to 13) [17]; a visual analogue scale (VAS) on patient discomfort (graduated from 0 to 100 by patients, with higher scores indicating greater discomfort); a VAS on treatment satisfaction (graduated from 0 to 100 by patients, with higher scores indicating greater satisfaction); and any correlation between IPSS and the other variables. The cumulative distribution of patients as a function of the mean change in IPSS at 24 weeks was also evaluated. Baseline sexual function data were collected from answers to the following simple questions: 1. Are you sexually active?; 2. Now or during the last 3 months have you experienced: impotence, a decrease in libido 84

Variable Mean (SD): Age, years Total IPSS BII score VAS discomfort self-assessed by patients BPH symptom duration, months N (%): Symptom severity: mild (IPSS, 0–7) moderate (IPSS, 8–19) severe (IPSS, 20–35) Previous treatments α-blockers phytotherapy α-blockers phytotherapy other Sexually active within the last 3 months: ED Decrease in libido Ejaculation disorders

or any ejaculation disorders? The safety profile of dutasteride was analysed during the 24-week treatment and 16-week follow-up. The efficacy analysis included all enrolled patients who received at least one study treatment dose and for whom data on at least one of the efficacy endpoints was available. The safety analysis included all patients who received at least one study treatment dose. Estimation of the sample size, using a logistic regression method [18], was based on previous results [19,20] and the following assumptions: the probability of a patient with the mean baseline discomfort failing to achieve at least a 3-point IPSS decrease is 35%; and the odds ratio for a patient with baseline discomfort one SD above the mean failing to achieve a 3-point IPSS decrease is 1.4. This calculation showed that to achieve a significance level of 5% and power of 90%, a total of 382 patients was required. Baseline predictive factors for at least a 3-point decrease of IPSS found to be significant in univariate regression analyses were introduced into multivariate logistic regression analyses. Two regressions were used, one with baseline IPSS as a continuous variable and one with baseline IPSS as a discrete variable. Voiding and storage symptom subscores were only included in the model with IPSS as a discrete variable.

Value

TABLE 1 Baseline characteristics (366 patients)

66 (8.1) 15.3 (6.4) 5.1 (2.9) 48.9 (20.0) 43.1 (39.4)

48 (13) 216 (59) 102 (28) 218 (60) 113 (52) 62 (28) 35 (16) 8 (4) 273 (75) 107 (29) 110 (30) 60 (17)

RESULTS In all, 400 patients were recruited at 72 centres in France between April 2003 and September 2004; of these, 399 were included in the safety analysis and 366 in the efficacy analysis. Of the 399 patients, 72 (18%) withdrew from the study; the reasons for withdrawal included adverse events (11%), consent form withdrawal (3%), lost to followup (